Spatiotemporal analysis of glioma heterogeneity reveals Col1A1 as an actionable target to disrupt tumor mesenchymal differentiation, invasion and malignancy

Comba, Andrea; Syed, Farhatullah; Dunn, Patrick; Argento, Anna E; Hollon, Todd C.; Al-Holou, Wajd N.; Varela, Maria L.; Zamler, Daniel; Quass, Gunnar L; Apostolides, Pierre F.; Brown, Christine E.; Kish, Phillip E.; Kahana, Alon; Kleer, Celina G.; Motsch, Sébastien; Castro, María G.; Löwenstein, Pedro R.

doi:10.1101/2020.12.01.404970

Cited by 3 publications

(6 citation statements)

References 85 publications

(206 reference statements)

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“…Together with their capacity for collective motion, our data indicate that they likely contribute to tumor malignant behavior. Thus, we interpret oncostreams to be histological structures that represent areas of collective motion (113). As our data indicate that oncostream density correlates with tumor malignancy, we suggest that they are characteristic pathological components of gliomas.…”

Section: Tumoral Dynamic Heterogeneity Patterns Across Histologic Featuressupporting

confidence: 50%

“…Intratumoral microenvironment-specific expression from the IvyGAP atlas also advocated potential therapeutic avenues by identifying brain tumor initiating cells and target genes within individual anatomical regions (124,125). Our recent study proposed an improved laser scanning microdissection methodology to study the gene expression pattern of multicellular mesenchymal-like structures within the glioma tumor core and at the invasion front (113,(125)(126)(127)(128).…”

Section: The Gbm Molecular Landscape: Current and Futures Perspectives In Methodologies To Analyze Gbm With Spatial Resolutionmentioning

confidence: 99%

“…Gliomas are characterized by intratumoral heterogeneity and diffuse invasion into the healthy parenchyma. In doing so, gliomas use various motility patterns, i.e., single cell invasion or collective invasion (Figure 1) (109)(110)(111)(112)(113). Tumor growth and invasion is usually considered to be a stochastic.…”

Section: Tumoral Dynamic Heterogeneity Patterns Across Histologic Featuresmentioning

confidence: 99%

“…Thus, the existence of organized dynamic structures in tumors, and what role they may play in tumor progression remains poorly elucidated (114). We recently characterized the complex dynamics of glioma cells in both the tumor core and at the tumor invasive borders, using mouse glioma explants from genetically engineered mouse models (111,113). We recently found that collective motion of tumor cells can be identified histologically as fascicles of aligned spindle-like and mesenchymallike tumor cells.…”

Section: Tumoral Dynamic Heterogeneity Patterns Across Histologic Featuresmentioning

confidence: 99%

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Uncovering Spatiotemporal Heterogeneity of High-Grade Gliomas: From Disease Biology to Therapeutic Implications

et al. 2021

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Glioblastomas (GBM) are the most common and aggressive tumors of the central nervous system. Rapid tumor growth and diffuse infiltration into healthy brain tissue, along with high intratumoral heterogeneity, challenge therapeutic efficacy and prognosis. A better understanding of spatiotemporal tumor heterogeneity at the histological, cellular, molecular, and dynamic levels would accelerate the development of novel treatments for this devastating brain cancer. Histologically, GBM is characterized by nuclear atypia, cellular pleomorphism, necrosis, microvascular proliferation, and pseudopalisades. At the cellular level, the glioma microenvironment comprises a heterogeneous landscape of cell populations, including tumor cells, non-transformed/reactive glial and neural cells, immune cells, mesenchymal cells, and stem cells, which support tumor growth and invasion through complex network crosstalk. Genomic and transcriptomic analyses of gliomas have revealed significant inter and intratumoral heterogeneity and insights into their molecular pathogenesis. Moreover, recent evidence suggests that diverse dynamics of collective motion patterns exist in glioma tumors, which correlate with histological features. We hypothesize that glioma heterogeneity is not stochastic, but rather arises from organized and dynamic attributes, which favor glioma malignancy and influences treatment regimens. This review highlights the importance of an integrative approach of glioma histopathological features, single-cell and spatially resolved transcriptomic and cellular dynamics to understand tumor heterogeneity and maximize therapeutic effects.

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Section: Tumoral Dynamic Heterogeneity Patterns Across Histologic Featuressupporting

confidence: 50%

Section: The Gbm Molecular Landscape: Current and Futures Perspectives In Methodologies To Analyze Gbm With Spatial Resolutionmentioning

confidence: 99%

Section: Tumoral Dynamic Heterogeneity Patterns Across Histologic Featuresmentioning

confidence: 99%

Section: Tumoral Dynamic Heterogeneity Patterns Across Histologic Featuresmentioning

confidence: 99%

See 2 more Smart Citations

Uncovering Spatiotemporal Heterogeneity of High-Grade Gliomas: From Disease Biology to Therapeutic Implications

et al. 2021

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“…Recent studies indicate the role of macrophages in inducing glioma mesenchymal-like states through stimulation of Oncostatin-M (OSM) and its receptor OSMR, resulting in STAT3 activation ( 35 ). Additionally, another recent study shows that COL1A1 inhibition in glioma cells decreased CD68+ and IBA1+ macrophages/microglia within the tumor, decreased mesenchymal transformation, and inhibited tumor growth ( 36 ).…”

Section: Tumor Microenvironment In High-grade Gliomamentioning

confidence: 99%

Development of immunotherapy for high-grade gliomas: Overcoming the immunosuppressive tumor microenvironment

et al. 2022

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The preclinical and clinical development of novel immunotherapies for the treatment of central nervous system (CNS) tumors is advancing at a rapid pace. High-grade gliomas (HGG) are aggressive tumors with poor prognoses in both adult and pediatric patients, and innovative and effective therapies are greatly needed. The use of cytotoxic chemotherapies has marginally improved survival in some HGG patient populations. Although several challenges exist for the successful development of immunotherapies for CNS tumors, recent insights into the genetic alterations that define the pathogenesis of HGG and their direct effects on the tumor microenvironment (TME) may allow for a more refined and targeted therapeutic approach. This review will focus on the TME in HGG, the genetic drivers frequently found in these tumors and their effect on the TME, the development of immunotherapy for HGG, and the practical challenges in clinical trials employing immunotherapy for HGG. Herein, we will discuss broadly the TME and immunotherapy development in HGG, with a specific focus on glioblastoma multiforme (GBM) as well as additional discussion in the context of the pediatric HGG diagnoses of diffuse midline glioma (DMG) and diffuse hemispheric glioma (DHG).

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Editorial: Spatiotemporal heterogeneity in CNS tumors

Faisal,

Ravi,

Miska

2024

Front. Immunol.

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Central nervous system (CNS) tumors, particularly gliomas such as glioblastoma (GBM), have the worst prognosis. The median survival time was only 14-16 months. This is largely due to their immunosuppressive tumor microenvironment (TME) and pronounced heterogeneity at the spatial, temporal, cellular and molecular levels (1-3). The intricate crosstalk of cellular and molecular spatiotemporal heterogeneity within these tumors presents significant challenges for developing effective treatment strategies (2-4).Recent advancements, such as the introduction of spatially resolved T cell receptor sequencing (SPTCR-seq) by Benotmyane et al., highlight the rapid evolution of our analytical methods. This technique utilizes optimized target enrichment and long-read sequencing to surpass existing technologies in reconstructing complete TCR architectures and evaluating T cell diversity in cancer. This progress advances our understanding of cancer immunosuppression and signals a broader trend in the field. In addition to spatial analysis, new methodologies are emerging, driving us toward significant clinical benefits. As these technologies continue to evolve, we are optimistic that the coming years will see these innovations translate into noticeable improvements in patient outcomes, indicating that we are moving in the right direction (5).Gene therapy is experiencing a resurgence, highlighted by the recent approval of Todo's oncolytic HSV-1 G47D gene therapy in Japan. This marked a significant milestone in the treatment of residual or recurrent GBM, where Todo et al.'s phase I and II clinical trials have demonstrated promising results, including encouraging one-year survival rates. These trials incorporated histopathological analysis of matched samples taken from primary surgery before treatment and from secondary surgery posttreatment, revealing enhanced recruitment of immune cells in the secondary tissue following gene therapy (6, 7). Furthering this line, Umemura and coauthors employed multiplex spatial analysis in their phase 1 clinical trial to map the distribution of tumor cells, immune cells, and other cellular constituents within the glioma microenvironment. Their findings suggested a significant increase in the immune region characterized by a high density of CD45 + lymphocytes in six out of eight patients following dual viral vector Ad-TK and Ad-Flt3L-based gene therapy (8). Conversely, the tumor region, identified by a high density of SOX2 + tumor cells, showed a decrease in all patients. Interestingly, the analysis revealed that immune cells are often entrapped by myeloid cells in Frontiers in Immunology frontiersin.org 01

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Spatiotemporal analysis of glioma heterogeneity reveals Col1A1 as an actionable target to disrupt tumor mesenchymal differentiation, invasion and malignancy

Cited by 3 publications

References 85 publications

Uncovering Spatiotemporal Heterogeneity of High-Grade Gliomas: From Disease Biology to Therapeutic Implications

Uncovering Spatiotemporal Heterogeneity of High-Grade Gliomas: From Disease Biology to Therapeutic Implications

Development of immunotherapy for high-grade gliomas: Overcoming the immunosuppressive tumor microenvironment

Editorial: Spatiotemporal heterogeneity in CNS tumors

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